Abstract

Context:

Testosterone (T) is commonly administered intramuscularly to treat hypogonadal males and female-to-male (FTM) transgender patients. However, these injections can involve significant discomfort and may require arrangements for administration by others.

Objective:

We assessed whether T could be administered effectively and safely subcutaneously as an alternative to intramuscular (IM) injections.

Testosterone (T) therapy is commonly administered to hypogonadal men and female-to-male (FTM) transgender patients. Since its introduction in the 1930s, parenteral T has typically been administered intramuscularly (
1
,
2
). However, intramuscular (IM) administration of T has drawbacks such as pain, bruising, and the frequent necessity to arrange injections by a medical provider or other person. T undeconoate provides an option for IM injections at 10-week intervals but is available only through a risk evaluation and mitigation program because of the risk of pulmonary oil microembolism (
3
–
5
). Transdermal T formulations (patches and gels) can also have limitations such as local reactions, poor adhesion, fear of skin-to-skin transmission (
6
), unpleasant odor (
7
), lack of insurance coverage or high copays, and limited patient acceptance (
8
). Subcutaneous (SC) insertion of T pellets is available but has been limited by the need for surgery, the possibility of infection, fibrosis or pellet extrusion, limited data regarding efficacy, inflexibility of dosing, and limited acceptance (
9
).

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"It's so hard to give up on something you are so proud of and that worked for so long," says Dos Equis senior brand director Quinn Kilbury, noting that the Most Interesting Man "helped grow the brand from a very small regional brand to a bit of a national power." But "It became too much about him," he says. "We really wanted to make that shift from the most interesting man to the most interesting beer."

He adds: "We didn't kill the man. So who knows, somewhere in the future maybe he comes back to play with us again, but not until we establish the brand on its own."

Of late, Dos Equis has struggled. Beer Business Daily recently reported that Dos Equis "is off to a rather lousy start in 2018," citing Nielsen data showing sales volume of the brand franchise down 5.8 percent year-to-date as of Feb. 17.

Scott Bell, executive creative director at Droga5, said inheriting a classic campaign like the Most Interesting Man is a "mix of terror and excitement." The agency, he says, took the approach of evaluating "what interesting means today" and "not getting caught up in how people feel about the Most interesting Man and or if people wanted to see another version of it."

Figure 4

Time course of (a) mprA-gfp and (b) sigE-gfp expression
. harboring the appropriate promoter construct was grown for different periods of time (indicated in hours (h)) and the specific promoter-driven expression of GFP was monitored by flow cytometry. With time, there is a gradual transition from the L to the H subpopulation.

Analysis of the time course of gfp expression
. (a) Mean protein level in L subpopulation (basal level) versus time in hours in the three cases of fused with , and promoters respectively. (b) Fraction of cells (t) in the H subpopulation versus time in hours in the three cases. (c) Transition rate from the L to the H subpopulation and the CV (experimental data shown) of the protein levels in the L subpopulation versus time in hours in the three cases. The experimental data are analyzed using the binning algorithm to obtain the plots (a), (b) and (c).

Figure S4 (Additional File
1
) shows the plots of mean GFP fluorescence level for the total population versus time in the three cases of
gfp
fused with the promoters of
mprA
,
sigE
and
rel
respectively. As in the case of the basal level versus time data (Figure
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), the plots are sigmoidal in nature. We solved the differential equations of the theoretical model described in Additional File
1
and obtained the concentrations of MprA, MprB, SigE, MprA-P, MprB-P and GFP versus time. Some of these plots are shown in Figure S5 (Additional File
1
) and reproduce the sigmoidal nature of the experimental plots. We note that the sigmoidal nature of the curves is obtained only when the non-linear nature of the degradation rate is taken into account.

As we have already discussed, the distribution of GFP levels in the mycobacterial cell population is a linear combination of two invariant distributions, one Gaussian and the other lognormal, with only the coefficients in the linear combination dependent on time. Friedman et al. [
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] have developed an analytical framework of stochastic gene expression and shown that the steady state distribution of protein levels is given by the gamma distribution. The theory was later extended to include the cases of transcriptional autoregulation as well as noise propagation in a simple genetic network. While experimental support for gamma distribution has been obtained earlier [
44
], a recent exhaustive study [
45
] of the
E. coli
proteome and transcriptome with single-molecule sensitivity in single cells has established that the distributions of almost all the protein levels out of the 1018 proteins investigated, are well fitted by the gamma distribution in the steady state. The gamma distribution was found to give a better fit than the lognormal distribution for proteins with low expression levels and almost similar fits for proteins with high expression levels. We analysed our GFP expression data to compare the fits using lognormal and gamma distributions. For all the three sets of data (
gfp
fused with the promoters of
mprA
,
sigE
and
rel
), the lognormal and gamma distribution give similar fits at the different time points. Figure S6 (Additional File
1
) shows a comparison of the fits for the case of
gfp
-
mprA
. The lognormal appears to give a somewhat better fit than the gamma distribution, specially at the tail ends.